Derivatives of p-substituted phenyl ester of pivalic acid

ABSTRACT

A derivative of general formula: ##STR1## wherein Y is --SO 2  -- or ##STR2## (i) R 1  and R 2 , which may be the same or different, each represent, (1) --H, (2) C1-16 alkyl or (3) the formula: --X-- ○A --(R 4 ) n  wherein X is a single-bond, --SO 2  --, C1-4 alkylene, C1-4 alkylene substituted by ##STR3##  -- ○A -- is carbocyclic or heterocyclic ring, n is 1˜5, R 4  is (1) --H or C1-8 alkyl, (2) C1-14 alkoxy, (3) C1-6 alkylthio, (4) --OH, halogen, --NO 2  or trihalomethyl, (5) the formula: --NR 41  R 42  wherein R 41  and R 42  each represents halogen or C1-4 alkyl, (6) tetrazole, (7) --SO 3  H or --CH 2  OH, (8) the formula: --SO 2  NR 41  R 42  (9) the formula: --Z 41  --COOR 43  wherein Z 41  is single-bond, C1-4 alkylene or C2-4 alkenylene, R 43  is --H, C1-4 alkyl or benzyl, (10) the formula: --CONR 41  R 42  (11) the formula: --COO--Z 42  --COOR 43  wherein Z 42  is C1-4 alkylene, R 43  is --H, C1-4 alkyl or benzyl, (12) the formula: --COO--Z 42  --CONR 41  R 42  (13) the formula: --OCO--R 45  wherein R 45  is C1-8 alkyl or p-guanidinophenyl, (14) the formula: --CO--R 46  wherein R 46  is C1-4 alkyl, (15) the formula: --O--Z 43  --COOR 450  wherein Z 43  is C1-6 alkylene, R 450  represents a hydrogen, C1-8 alkyl or p-guanidinophenyl, (16) the formula: ##STR4##  wherein ##STR5##  is an amino acid residue, R 47  is bond, C1-4 alkyl, R 48  is --H or C1-4 alkyl, R 49  is --OH, C1-4 alkoxy, --NH 2 , amino substituted by one or two C1-4 alkyl, carbamoylmethoxy or carbamoylmethoxy substituted by one or two C1-4 alkyl at N atom of carbamoyl, wherein ##STR6##  is C3-6 heterocyclic ring, (ii) R 1 , R 2  and N atom bonded to R 1  and R 2  together represents heterocyclic ring containing at least a N atom(s) and substituted by --COOH or unsubstituted heterocyclic ring containing at least a N atom(s), R 3  is (1) --H, (2) --OH, (3) C1-6 alkyl, (4) halogen, (5) C1-4 alkoxy or (6) C2-5 acyloxy, m is 1-4. 
     or non-toxic salt or an acid addition salt thereof possess inhibitory activity on elastase, and therefore is useful for treating and/or preventing agent for pulmonary emphysema, atherosclerosis and rheumatoid arthritis and the like.

SUMMARY

This invention is related to the derivatives of p-substituted phenyl ester of pivalic acid having an inhibitory activity on elastase, of the general formula: ##STR7## wherein R¹, R², R³, Y and m have same meaning as described hereinafter.

BACKGROUND

Lysosomal hydrolases of neutrophils have an important role for an organism defense reaction against tissue damage caused by microbe or inflammation etc.

Elastase and cathepsin G, which belong to neutral serine proteinase locally existed in azurophil granule mainly play a part in decomposition of a connective tissue.

Especially, elastase degrades elastic connective tissue by cleaving the cross-linking of elastin which directly maintains the elasticity of lung tissue etc., and by cleaving hydrophobic part of protein [J. Cell. Biol., 40, 366 (1969)] and degrades the cross-linking area of collagen selectively as well as elastin [J. Biochem., 84, 559 (1978)], and it acts on tissue proteins such as proteoglycans etc. [J. Clin. Invest., 57, 615 (1976)]. Therefore, elastase plays an important role in metabolism of connective tissue.

Elastase is inactivated by α₁ -proteinase inhibitor (α₁ -PI) that is a common inhibitor for serine, proteinase in vivo and the unbalance of enzyme and inhibitor system causes the destruction of the tissue [Schweiz. Med. Wshr., 114, 895 (1984)].

The turnover of elastin in normal tissue is very slow [Endocrinology, 120, 92 (1978)], but the pathological acceleration in degradation of elastin is found under various unsound state such as pulmonary emphysema [Am. Rev. Respir. Dis., 110, 254 (1974)], atherosclerosis [Lab. Invest., 22, 228 (1970)] and rheumatoid arthritis [in Neutral Proteases of Human Polymorphonuclear Leukocytes, Urban and Schwarzenberg, Baltimore - Munich (1978), page 390], suggesting the relationship of elastase and diseases [Infection.Inflammation.Immunity, 13, 13 (1983)].

PRIOR ARTS

Under the background as mentioned above, recent studies and development on elastase inhibitors have been heartily conducted, and various substances inhibiting elastase have been proposed and many patent applications have been filed.

Particularly, recently, for example, in the specification of U.S. Pat. No. 4,683,241, the compound of the general formula: ##STR8## wherein Xa represents a group selected from carbonyl group, methylene group, oxygen atom, azo group, sulfonyl group, --CH(OH)--, together with the benzene rings represents the group ##STR9## R^(a) and R^(1a) each represents an alkyl group and an acylaminoalkyl group of 2 to 6 carbon atoms, an alkoxy group, an alkenyl group and carboxyalkyl group of up to 6 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms or an alkoxycarbonylalkyl group of up to 10 carbon atom(s), R^(2a) and R^(3a) represent hydroxy atom, halogen atom, pyranyloxy, an alkyl, an alkenyl, hydroxyalkyl and formylalkyl group of up to 4 carbon atom(s) or carboxyalkyl group of up to 6 carbon atom(s), was disclosed.

PURPOSE OF THE INVENTION

As the result of energetic investigations conducted in order to find new elastase inhibitory agents having quite different chemical structure from conventional ones, the present inventors have found that the compound of the general formula (I) achieves this purpose.

COMPARISON WITH THE PRIOR ARTS

In the specification of U.S. Pat. No. 4,683,241, benzoylphenyl ester and benzenesulfonylphenyl ester of any kind pivalic acid were disclosed as the inhibitory agent on elastase.

The structure of sulfamoylphenyl ester and carbamoylphenyl ester in the present invention can not be obvious from compounds of the Prior Art, and it have been unexpected that compounds of the present invention have inhibitory effect on elastase.

DISCLOSURE OF THE INVENTION

Accordingly, the present invention relates to the compounds of the general formula: ##STR10## wherein Y represents sulfonyl (--SO₂ --) group or carbonyl ##STR11## (i) R¹ and R², which may be the same or different, each represent

(1) hydrogen atom,

(2) an alkyl group of up to 16 carbon atom(s) or an alkyl group of up to 16 carbon atom(s) substituted by carboxy group

(3) a group of the formula: --X-- ○A --(R⁴)_(n)

wherein X represents single-bond, sulfonyl (--SO₂) group, an alkylene group of up to 4 carbon atom(s) or an alkylene group of up to 4 carbon atom(s) substituted by --COOH group or benzyloxycarbonyl ##STR12## -- ○A -- represents carbocyclic ring or heterocyclic ring, n represents an integer of 1 to 5,

R4 represents, same or different,

hydrogen atom or an alkyl group of up to 8 carbon atom(s),

an alkoxy group of up to 14 carbon atom(s),

an alkylthio group of up to 6 carbon atom(s),

hydroxy group, halogen atom, nitro group or trihalomethyl group,

a group of the formula: --NR⁴¹ R⁴² wherein R⁴¹ and R⁴² each represents, same or different, hydrogen atom or alkyl group of up to 4 carbon atom(s),

tetrazole group,

sulfonic acid (--SO₃ H) group or hydroxymethyl (--CH₂ OH) group,

a group of the formula: --SO₂ NR⁴¹ R⁴² wherein R⁴¹ and R⁴² have the same meaning as described hereinbefore,

a group of the formula: --Z⁴¹ --COOR⁴³ wherein Z⁴¹ represents single-bond, an alkylene group of up to 4 carbon atom(s) or an alkenylene group of from 2 to 4 carbon atoms,

R⁴³ represents hydrogen atom, an alkyl group of up to 4 carbon atom(s) or benzyl group,

a group of the formula: --CONR⁴¹ R⁴² wherein R⁴¹ and R⁴² have same meaning as described hereinbefore,

a group of the formula: --COO--Z⁴² --COOR⁴³ wherein Z⁴² represents an alkylene group of up to 4 carbon atom(s),

R⁴³ represents hydrogen atom, an alkyl group of up to 4 carbon atom(s) or benzyl group,

a group of the formula: --COO--Z⁴² --CONR⁴¹ R⁴² wherein Z⁴², R⁴¹ and R⁴² have same meaning as described hereinbefore.

a group of the formula: --OCO--R⁴⁵ wherein R⁴⁵ represents an alkyl group of up to 8 carbon atom(s) or p-guanidinophenyl group,

a group of the formula: --CO--R⁴⁶ wherein R⁴⁶ represents an alkyl group of up to 4 carbon atom(s),

a group of the formula: --O--Z⁴³ --COOR⁴⁵⁰

wherein Z⁴³ represents an alkylene group of up to 6 carbon atom(s).

R⁴⁵⁰ represents a hydrogen atom, an alkyl group of up to 8 or p-guanidinophenyl group,

a group of the formula: ##STR13## wherein ##STR14## represents an amino acid residue, R⁴⁸ represents hydrogen atom or alkyl group of up to 4 carbon atom(s), and R⁴⁹ represents hydroxy group, alkoxy group of up to 4 carbon atom(s), amino group, amino group substituted by one or two alkyl group of up to 4 carbon atom(s), carbamoylmethoxy or carbamoylmethoxy group substituted by one or two alkyl group of up to 4 carbon atoms at nitrogen atom of carbamoyl group, R⁴⁷ represents single-bond or alkyl group of up to 4 carbon atom(s), or wherein ##STR15## represents heterocyclic ring containing 3 to 6 carbon atoms and R⁴⁷ and R⁴⁹ has each same meaning as described hereinbefore,

(ii) R¹, R² and nitrogen atom bonded to R¹ and R₂ together represents heterocyclic ring containing at least one nitrogen atom(s) and substituted by --COOH, or unsubstituted heterocyclic ring containing at least one nitrogen atom(s),

R³ represents

(1) hydrogen atom,

(2) hydroxy atom,

(3) an alkyl group of up to 6 carbon atom(s),

(4) halogen atom,

(5) an alkoxy group of up to 4 carbon atom(s) or

(6) an acyloxy group of 2 to 5 carbon atoms,

m represents an integer of up to 4,

or non-toxic salts or acid addition salts thereof or process for the preparation thereof, or inhibitory agents of elastase containing them as active ingredient.

In this specification and claims, the term "alkyl group", "alkylene group", "alkenylene group", "alkoxy group" and "acyloxy group" means the straight- or branched- chained alkyl group, alkylene group, alkenylene group, alkoxy group and acyloxy group.

In the general formula (I), sulfonyl and carbonyl group represented by Y are preferred.

In the general formula (I), as an alkyl group of up to 6 carbon atom(s) represented by R³, methyl, ethyl, propyl, butyl, pentyl and hexyl group and the isomer thereof are cited, and all of them are preferred.

In the general formula (I), examples of the halogen atom, represented by R³ and R⁴ are, a fluorine atom, a chlorine atom, a bromine atom and an iodine.

In the general formula (I), examples of an alkoxy group of up to 4 carbon atom(s) represented by R³, include methoxy, ethoxy, propoxy and butyloxy group and the isomer thereof, and all of them are preferred.

In the general formula (I), examples of an acyloxy group of 2 to 5 carbon atom(s) represented by R³, include acetoxy, propionyloxy, butyryloxy and valeryloxy group and the isomer thereof are cited, and all of them are preferred.

In the general formula (I), examples of an alkyl group of up to 16 carbon atom(s) represented by R¹ and R², include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl group and the isomer thereof, and all of them are preferred.

In the general formula (I), examples of an alkylene group of up to 4 carbon atom(s) represented by X and Z⁴¹, include methylene, ethylene, trimethylene and tetramethylene group and the isomer thereof, and all of them are preferred.

In the general formula (I), carbocyclic ring represented by ○ means mono- or bi-aromatic carbocyclic ring(s) containing not more than 12 carbon atoms which may be partially or fully saturated rings thereof.

Examples of these rings mentioned above are benzene, naphthalene, indene, azulene rings and partially or fully saturated rings thereof.

In the general formula (I), heterocyclic ring represented by ○ means mono-, bi-aromatic heterocyclic ring(s) containing not more than 12 carbon and hetero atoms which may be partially or fully saturated rings thereof. In above heterocyclic rings, rings containing one or two of hetero atom(s) are preferred.

Examples of these rings mentioned above are furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazane, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, benzothiophen, indolidine, chromen, quinoline, isoquinoline, quinolidine, purine, indazole, quinazoline, cinnoline, quinoxaline, phthalazin, pteridine rings and partially or fully saturated rings thereof.

In the general formula (I), examples of an alkyl group of up to 8 carbon atom(s) represented by R⁴, include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and the isomer thereof are cited, and all of them are preferred.

In the general formula (I), examples of an alkoxy group of up to 14 carbon atom(s) represented by R⁴, include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy and tetradecyloxy group and the isomer thereof, and all of them are preferred, but particularly preferred are methoxy, pentyloxy, decyloxy and the isomer thereof.

In the general formula (I), examples of an alkylthio group of up to 6 carbon atom(s) represented by R⁴, include methylthio, ethylthio, propylthio, butylthio, pentylthio and hexylthio group and the isomer thereof, and all of them are preferred.

In the general formula (I), as R⁴, halogen, trihalomethyl, nitro, hydroxy, tetrazole, sulfonic acid and hydroxymethyl are particularly preferred.

In the general formula (I), examples of an alkyl group of up to 4 carbon atom(s) represented by R⁴¹, R⁴², R⁴³ and R⁴⁶, include methyl, ethyl, propyl and butyl group and the isomer thereof, and all of them are preferred.

In the general formula (I), examples of an alkenylene group of 2 to 4 carbon atom(s) represented by Z⁴¹, include vinylene, propenylene and butenylene group and the isomer thereof, and all of them are preferred.

In the general formula (I), examples of an alkyl group of up to 8 carbon atom(s) represented by R⁴⁵, include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl group and the isomer thereof, and all of them are preferred.

In the general formula (I), examples of an alkylene group of up to 6 carbon atom(s) represented by Z⁴³, include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene group and the isomer thereof, and all of them are preferred.

In the general formula (I), an amino acid -residue represented by formula: ##STR16## represents every amino acid-residue, and these residues contain that carboxy group was converted into ester.

Preferable amino acid-residue is neutral, acidic or basic amino acid-residue. Examples of the residues mentioned above include glycine, alanine, β-alanine, valine, phenylalanine, lysine, methionine, tyrosine, proline, leucine, tryptophan, 4-amino butyric acid, 6-aminocaproic acid, 1-amino-1-phenylacetic acid, 2-amino-2-phenylpropionic acid, m-aminobenzoic acid, p-aminobenzoic acid.

Examples of an alkyl group of up to 4 carbon atom(s) represented by R⁴⁸, include methyl, ethyl, propyl and butyl group and the isomer thereof. Included as exemplary of an alkyl, in alkoxy group represented by R⁴⁹, in substituent of amino group and in substituent of carbamoylmethoxy group, methyl, ethyl, propyl and butyl group and the isomer thereof. Exemplary of the heterocyclic ring represented by ##STR17## are azetidine, pyrrolidine, piperidine and perhydroazepine.

In the general formula (I), the heterocyclic ring represented by R¹, R² and the nitrogen atom bonded to R¹ and R² together, means a mono- heterocyclic ring containing 3 to 6 carbon atoms and 1 or 2 of nitrogen and/or oxygen atom(s).

Examples of these rings mentioned above are pyrrole, imidazole, pyrazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, azetidine.

An acid addition salts of the compound of the general formula (I) are preferred non-toxic and water-soluble salts.

Suitable acid addition salts include, for example, an inorganic acid addition salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or an organic acid addition salt such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate.

The compounds of the present invention of the general formula (I) may be converted into the corresponding salts by known methods. Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are as follows: salts of alkaline metal (sodium, potassium etc.), salts of alkaline earth metal (carcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amine (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidineamine, monoethanolamine, diethanolamine, tris (hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine etc.)

PROCESS FOR THE PREPARATION

According to the present invention, the compounds of the present invention of the general formula (I) may be prepared by any step described hereinafter.

In each formula,

R¹¹ and R²¹ have same meaning as that of R¹ and R², respectively provided that at least either R¹¹ or R²¹ represents benzyloxycarbonyl group,

R¹² and R²² have same meaning as that of R¹ and R², respectively provided that at least either R¹² or R²² represents carboxyl group,

R¹³ has same meaning that of R¹ or R² other than hydrogen atom,

R¹⁴ represents an alkyl group of up to 4 carbon atom(s), X represents halogen atom,

R³¹ represents an acyloxy group. ##STR18##

Step 1, which is an esterification reaction, conducted in the presence of a dehydrohalogenation agent in inert organic solvents (for example, methylene chloride, ethyl acetate, benzene, hexane, diethylether), may be carried out by reacting with corresponding pivaloyl halide under room temperature.

As for the dehydrohalogenation agent, there can be used a tertiary organic amine, or if desired, there can be used a inorganic base such as a metal bicarbonate, etc.

As a tertiary organic amine, there can be used aliphatic, aromatic or heterocyclic amine, for example, triethylamine, tributylamine, dimethylaniline, pyridine and the like.

Particularly, pyridine is preferable because it is useful also as a solvent of reaction ingredient.

Step 2, which is reaction forming the amide-bond, may be carried out by reacting the compound of the general formula (III) with corresponding amine in inert organic solvent (for example methylene chloride), in the presence of organic or inorganic base (for example, tertiary amine such as triethylamine), at a temperature of -20° C.˜0° C. (preferably under cooling with ice).

Step 3, which is reaction for removing a benzyl group, may be carried out under an atmosphere of hydrogen gas, using palladium-carbon as catalyst in a mixture of inert organic solvent (for example acetic acid, THF), at a temperature of 0° C. to 40° C.

Step 4, which is N-alkylation reaction, may be carried out reacting with alkyl halide in suitable inert organic solvent (for example, benzene, tetrahydrofuran, dimethylformamide), in the presence of a suitable base (for example, sodium hydride), at from about room temperature to reflux temperature.

Step 5, which is reaction for eliminating the acyl group, may be carried out for example, in methanol, in the presence of a catalyst (for example, triethylamine), at or about room temperature.

The compounds of the general formula (II) and (III) used in the step hereinbefore may be prepared by combining known methods, for example according to scheme A hereinafter.

In the formula, G represents methoxy group or acetoxy group, and the other symbols have same meaning as described hereinbefore. ##STR19##

All reactions in the above schemes may be carried out by known methods.

In each reaction in the present specification, products may be purified by conventional manner. For example, purification may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions.

STARTING MATERIALS

The starting materials of formula (IV), (V) and (VII) in Scheme A are known compounds, or may be easily prepared by known methods.

For example, when R¹ and R² in the formula (IV) each represents R¹ and (3)- 16 of R² in the formula (I) mentioned above, those may be prepared according to scheme B described hereinafter.

In the formula, the sum of p and r represents an integer of 1 to 5, and r does not represent zero.

R²⁴ has same meaning that of R⁴ other than (3) -16. ##STR20##

EFFECT

Derivatives of p-substituted phenyl ester of pivalic acid of the general formula (I) of the present invention, and non-toxic acid and acid addition salts thereof, have an inhibitory effect on elastase.

Accordingly, the derivatives of the present invention are useful for treatment and/or prevention of diseases induced by the abnormal enhancing of the degradation of elastin, collagen fiber and/or proteoglican, by the action of elastase, in mammals, especially in human beings.

Examples of such diseases are pulmonary emphysema, atherosclerosis, rheumatoid arthritis and the like.

The inhibitory effects of the compounds of the invention on elastase were confirmed by the screening system disclosed below.

INHIBITORY EFFECT ON ELASTASE

(1) Method of experiment

The test was carried out by a slight modification of the method of Bieth et al [see Biochem. Med., 75, 350 (1974)] using elastase from human neutrophil.

Namely, it is a spectrophotometric method using the synthesized substrate [succinyl-alanyl-prolyl-alanyl-p-nitroanilide (Suc-Ala-Pro-Ala-pNA, produced by peptide laboratory)] which has comparatively high specificity on neutrophil elastase.

The reaction mixture consisted of 1 mM Suc-Ala-Pro-Ala-pNA (dissolving in N-methylpyrrolidone to the concentration of 100 mM, and then adding 1/100 amount of the solution to the reaction mixture.), 0.1 M buffer solution of tris-hydrochloric acid (pH 8.0), 0.2 M sodium chloride aqueous solution, the sample solution of various concentrations and enzyme solution in a final volume of 1.0 ml was incubated at 37° C. for 30 minutes.

The reaction was stopped by the addition of 100 μl of 50% acetic acid into the reaction mixture, and then p-nitro anilide released was measured on absorbance of 405 nm.

Inhibition percentage of the test compounds was calculated by the following equation: ##EQU1##

                                      TABLE I                                      __________________________________________________________________________     Inhibitory effect of elastase                                                  __________________________________________________________________________          Structure                                                                  No.Example                                                                          ##STR21##                   Name                   elastase                                                                      (μM)effect                                                                  ofInhibitory           __________________________________________________________________________           ##STR22##                  p-[N-(p-bromophenyl)-N-methylsulfamoyl]                                        phenyl ester of pivalic                                                                               0.031                  1(2)                                                                                 ##STR23##                  p-sulfamoylphenyl ester of pivalic                                                                    0.77                   1(3)                                                                                 ##STR24##                  p-(N-cyclohexylsulfamoyl)phenyl ester of                                       ivalic acid            0.042                  1(8)                                                                                 ##STR25##                  p-[N-(p-chlorophenyl)sulfamoyl]phenyl                                          ester of pivalic acid  0.03                   1(12)                                                                                ##STR26##                  p-[(1-imidazoyl)sulfonyl[phenyl ester of                                       ivalic acid            0.05                   1(14)                                                                                ##STR27##                  p-[N-(α-pyridyl)sulfamoyl]phenyl                                         ester of pivalic acid  0.19                   1(15)                                                                                ##STR28##                  1-acetoxy-4-[N,N-bis(p-pivaloyloxy-                                            phenylsulfonyl)amino]benzene                                                                          0.048                  2(5)                                                                                 ##STR29##                  p-(N-tert-butylsulfamoyl)phenyl ester of                                       ivalic acid            0.053                  2(38)                                                                                ##STR30##                  2-methyl-4-[N-(N,N- diethylcarbamoylmetho                                      xycarbonyl)phenyl) sulfamoyl]phenyl                                            ester of pivalic acid  0.072                  2(49)                                                                                ##STR31##                  2-methyl-4-[N-(1,4-dioxa-2-carboxy-8-yl-                                       aphthalene)sulfamoyl]phenyl ester of                                           pivalic acid           0.15                   2(51)                                                                                ##STR32##                  2-methyl-4-[N-(o-carboxypropoxyphenyl)                                         sulfamoyl]phenyl ester of pivalic                                                                     0.64                   2(62)                                                                                ##STR33##                  2-methyl-4-[N-(o-carbonylphenyl)                                               sulfamoyl]phenyl ester of pivalic                                                                     0.69                   2(63)                                                                                ##STR34##                  N-[O-(p-pivaloyloxybenzene) sulfonylamino                                      benzoyl]glycine        0.044                  __________________________________________________________________________          Structure                                                                  No.Example                                                                          ##STR35##                   Name                   elatase                                                                       (μM)effect                                                                  ofInhibitory           __________________________________________________________________________     2(67)                                                                                ##STR36##                  N-[O-(3-methyl-4- pivaloyloxybenzene)sulf     L- phenylanine                   onylaminobenzyoyl                                  0.41                                                                      2(68)                                                                                ##STR37##                  N-[O-(3-methyl-4-pivaloyloxybenzene)                                           sulfonylaminobenzoyl]-dl-methionine                                                                   0.20                   2(69)                                                                                ##STR38##                  N-[O-(3-methyl-4-pivaloyloxybenzene)                                           sulfonylaminobenzoyl]-L-lisine                                                 hydrochloride          0.52                   2(80)                                                                                ##STR39##                  N-[5-methylthio-2-(p-pivaloyloxybenzene)                                       ulfonylaminobenzoyl]glycine                                                                           0.021                  2(87)                                                                                ##STR40##                  N-[2-(p-pivaloyloxybenzene)sulfonylamino-                                      5- propylthiobenzoyl]glycine                                                                          0.024                  4(5)                                                                                 ##STR41##                  p-(N-phenethylsulfamoyl)phenyl ester of                                        pivalic acid           0.072                  5(3)                                                                                 ##STR42##                  p-[N-(o-carboxyphenyl)sulfamoyl]phenyl                                         ester of pivalic acid  0.023                  __________________________________________________________________________

The result of the experiment showed that the compounds of the present invention have an inhibitory effect on elastase.

TOXICITY

Further, it was confirmed that the toxicity of the compounds of the present invention is low enough such that they can be used safely for medical supplies.

APPLICATION

Accordingly, it was confirmed that the compounds of the present invention can be useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

ADMINISTRATION

For the purpose mentioned above, the compounds of the present invention, described in the general formula (I) or an acid addition salts thereof may normally be administered systemically or partially, usually by oral or parenteral administration.

The dose to be administered is determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person for one time are generally between 1 mg and 500 mg, by oral administration up to several times per day, and between 0.1 mg and 200 mg, by parenteral administration (preferably by intravenous administration) up to several times per day.

As mentioned above, the doses to be used depend on various conditions. Therefore, there are cases in which doses lower than the ranges specified above and doses greater than the ranges specified above, may be used.

Solid compositions according to the present invention for oral administration include compressed tablets, dispersible powders and granules. In such solid compositions, one or more of the active compound(s) is, or are, admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl-pyrrolidone or magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents e.g. lubricating agents such as magnesium stearate, and, disintegrating agents such as cellulose calcium glycolate, stabilizing agents such as lactose, and solubilizers such as glutamic acid and asparaginic acid. The tablets or pills may, if desired, be made into gastric film-coated or enteric film-coated tablets or pills, such as sugar-coated, gelatin-coated, hydroxypropylcellulose-coated or hydroxypropylmethylcellulose phthalate-coated tablets or pills; two or more layers may be used. The compositions for oral administration also include capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.

Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Besides inert diluents such compositions may also comprise stabilizers such as sodium bisulfite and buffer for isotonicity, for example sodium chloride, sodium citrate or citric acid.

The manufacturing methods of spray compositions have been described in detail, for example, in the specifications of U.S. Pat. Nos. 2,868,691 and 3,095,355.

Preparations for injection according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Example of aqueous solvents or suspending media are distilled water for injection and physiological salt solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (registered Trade Mark). These compositions may also include adjuvants such as preserving, wetting, emulsifying and dispersing agents stabilizing agents (e.g. lactose) and solubilizers (e.g. glutamic acid and asparaginic acid). They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Other compositions for parenteral administration include liquids for external use, and endermic liniments such as ointments, suppositories for rectal administration and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by known methods.

EXAMPLES AND COMPARATIVE EXAMPLES

The following Reference Examples and Examples illustrate the preparation of compounds of the present invention, however, the present invention is not restricted to them. In the Reference Examples and Examples, "TLC", "NMR" and "IR" each represents "thin layer chromatography", "nuclear magnetic resonance" and "infrared absorption spectrum", respectively.

The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separation.

Unless otherwise specified, "IR" were measured by KBr method, and "NMR" were measured in bichloroform (CDCl₃).

REFERENCE EXAMPLE 1 1-(N-methyl-N-phenyl)sulfamoyl-4-methoxybenzene ##STR43##

p-methoxybenzenesulfonyl chloride (965 mg) was dissolved in the mixture of triethylamine (2 ml), methylaniline (500 mg) and methylene chloride (10 ml) under cooling with ice, and the mixture was stirred for 30 minutes.

The reaction solution was stirred overnight at room temperature. After the reaction was finished, the reaction solution was extracted with ether. The extract was washed successively with 1N-HCl, water and a saturated aqueous solution of sodium chloride.

The solution was dried over sodium sulfate, and distilled off under reduced pressure to give the title compounds.

REFERENECE EXAMPLE 2 p-N-methyl-N-(p-bromophenyl)sulfamoyl]phenol ##STR44##

Boron tribromide (2.2 ml) was added to the solution of methylene chloride (10 ml) of the compound obtained by Reference Example 1 under cooling with ice, and stirred for 2 hours at room temperature.

The reaction solution was allowed to cool to -20° C.˜-30° C., and water was added thereto, and the solution obtained was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous solution of sodium chloride.

The solution was dried over sodium sulfate, and distilled off under reduced pressure and the residue was purified by column chromatography on silica-gel (methylene chloride: ethyl acetate=10:1) to give the title compound (900 mg) having the following physical data;

TLC: Rf 0.20 (methylene chloride: ethyl acetate=30:1).

REFERENCE EXAMPLE 3 p-[N-(p-tolyl)carbamoyl]phenol ##STR45##

Potassium carbonate (500 mg) was added into methanol solution (50 ml) of [p-acetoxy-N-(p-tolyl)]benzamide (300 mg) obtained by the same procedure as Reference Example 1, and the mixture was stirred overnight.

The obtained reaction solution was distilled off under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with 1N-hydroic acid, water and saturated aqueous solution of sodium chloride.

The solution was dried with magnesium sulfate, and distilled off under reduced pressure to give the title compound having the following physical data.

TLC Rf 0.31 (methylene chloride : ethyl acetate=10:1).

EXAMPLE 1 p-[N-(p-bromophenyl)-N-methylsulfamoyl]phenyl ester of pivalic acid ##STR46##

Pivaloyl chloride (0.5 ml) was added to the mixture solution of triethylamine (1.5 ml)-methylene chloride (5 ml) of the compounds obtained by procedure of Reference Example 2 under cooling with ice. The reaction solution was allowed to stand for 10 minutes, and stirred for one hour at room temperature.

The reaction solution was extracted with ether, and the extract was washed successively with water, 1N-HCl, water, saturated aqueous solution of sodium bicarbonate, water and saturated aqueous solution of sodium chloride. The solution was dried with sodium sulfate, and distilled off under reduced pressure.

The concentrate was recrystallized with ethyl acetate-hexane to give the title compound (510 mg) having the following physical data.

TLC: Rf 0.81 (methylene chloride : ethyl acetate=30:1);

IR: 1750, 1590, 1460, 1400, 1350 cm⁻¹.

Hereinafter, the title compound, which was described in the following Table II and III, was given by using corresponding starting materials and by operating the same procedure as Reference Example 1→Reference Example 2 (or Reference Example 3)→Example 1.

                                      TABLE II                                     __________________________________________________________________________      ##STR47##                                                                      No.Example                                                                          ##STR48##             Name               TLC    or NMRIR                 __________________________________________________________________________                                                          (cm.sup.-1)               1(1)                                                                                 ##STR49##            p-(N-phenylsulfamoyl)phenyl ester of pivalic                                   acid               Rf 0.3 (hexane: ethyl                                                          acetate: = 5:2)                                                                       δ 7.7(2H,d),                                                             7.3˜6.9(7H,m),                                                           .5(1H,6s), 1.3(9H,s)                                                           8                         1(2) NH.sub.2              p-sulfamoylphenyl ester of pivalic                                                                Rf 0.72                                                                               ν 3400,3280,1720,                                                           2                                                    acid               (hexane:                                                                              1580,1480,1350,                                                         ethyl acetate:                                                                        1200,1160,1120                                                          = 1:2)                           1(3)                                                                                 ##STR50##            p-(N-cyclohexylsulfamoyl)phenyl ester of                                       pivalic acid       Rf 0.82 (hexane: ethyl                                                         acetate: = 1:1)                                                                       ν 3280,2940,1750,                                                           590,1480,1440,                                                                 1320,1210,1160,                                                                1100                      1(4)                                                                                 ##STR51##            p-[N-(p-tolyl)sulfamoyl]phenyl ester of                                        pivalic acid       Rf 0.62 (methylene chloride:                                                    ethyl acetate: = 30:1)                                                               ν 3300,1740,1580,                                                           500,1380,1330,                                                                 1270,1200                 1(5)                                                                                 ##STR52##            p-[N-(p-benzyloxycarbonylphenyl) sulfamoyl]phen                                yl ester of pivalic acid                                                                          Rf 0.75 (hexane: ethyl                                                         acetate: = 1:1)                                                                       ν 1750,1720,1600,                                                           460,1340,1270,                                                                 1150,1100                 1(6)                                                                                 ##STR53##            p-[N-(4-N,N-dimethylamino)phenyl) sulfamoyl]phe                                nyl ester of pivalic acid                                                                         Rf 0.78 (hexane: ethyl                                                         acetate: = 1:2)                                                                       ν 1750,1610,1590,                                                           520,1330,1200,                                                                 1150,1100                 1(7) NHC.sub.10 H.sub.21   p-(N-decylsulfamoyl)phenyl ester                                                                  Rf 0.60                                                                               ν 3300,2930,2850,                                 pivalic acid       (methylene                                                                            1750,1590                                                               chloride:                                                                      ethyl acetate:                                                                 = 30:1)                          1(8)                                                                                 ##STR54##            p-[N-(4-chlorophenyl)sulfamoyl] phenyl ester                                   of pivalic acid    Rf 0.52 (methylene chloride:                                                    ethyl acetate: = 30:1)                                                               ν 3260,2970,1750,                                                           590,1490,1450, 1340       1(9)                                                                                 ##STR55##            p-[N-(m-chlorophenyl)sulfamoyl] phenyl ester                                   of pivalic acid    Rf 0.50 (methylene chloride:                                                    ethyl acetate: = 30:1)                                                               ν 3250,1750,1590,                                                           480,1400,1330, 1200       1(10)                                                                                ##STR56##            p-[N-(β-pyridyl)sulfamoyl]phenyl ester of                                 pivalic acid       Rf 0.50 (methylene chloride:                                                    methanol = 10:1)                                                                     ν 3600˜3200,                                                          1750, 1580,1470,1400                                                           3500,1310,1260,                                                                1200                      1(11)                                                                                ##STR57##            p-[N-(p-pentylphenyl)sulfamoyl] phenyl ester                                   of pivalic acid    Rf 0.46 methylene chloride:                                                    thyl acetate: = 30:1)                                                                  ν 3960,3920,3850,                                                           3250,1750,1610,                                                               1590,1510,1480,                                                                1460,1400,1330,                                                                (neat)                    1(12)                                                                                ##STR58##            p-[(1-imidazolyl)sulfonyl]phenyl ester of                                      pivalic acid       Rf 0.52 methylene chloride:                                                    thyl acetate: = 5:1)                                                                  δ 7.96(2H,d),8.                                                          0 (1H,m),7.28(2H,                                                              d),7.28(1H,m),                                                                 7.09(1H,m),1.36                                                                (9H,s)                    1(13)                                                                                ##STR59##            (p-morpholinosulfonyl)phenyl ester of pivalic                                  acid               Rf 0.19 (methylene chloride:                                                    ethyl acetate: = 30:1)                                                               ν 2970,2860,1759,                                                           590,1480,1340             1(14)                                                                                ##STR60##            p-[N-(α-pyridyl)sulfamoyl]phenyl ester                                   of pivalic acid    Rf 0.64 (chloroform:                                                           methanol: = 30:1)                                                                     ν 3200˜2300,                                                          1750, 1630,1610,1520,                                                           1490,1480,1460,                                                               1380,1360                 1(15)                                                                                ##STR61##            1-methoxy-4-[N,N-bis(p-  pivaloyloxyphenylsulfo                                nyl) amino]benzene Rf 0.61 (methylene chloride:                                                    ethyl acetate = 30:1)                                                                ν 3400,2970,1750,                                                           590,1480                  __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________      ##STR62##                                                                      No.Example                                                                          ##STR63##    Name              TLC       or NMRIR                        __________________________________________________________________________                                                   (cm.sup.-1)                       1(16)                                                                               ##STR64##   p-[N-(p-tolyl)carbamoyl]phenyl ester of pivalic                                                  Rf 0.46 (methylene chloride: ethyl                                             chloride: = 30:1)                                                                        ν 3300,2960,1740,                                                           1640,1600,1500                   __________________________________________________________________________

REFERENCE EXAMPLE 4 sodium salt of p-pivaloyloxybenzenesulfonic acid ##STR65##

Pivaloyl chloride (2.4 g) was dissolved in the mixture of 4N-aqueous solution of sodium hydroxide (7.5 ml) of phenol 4-sulfonic acid (1.74 g) and tetrahydrofuran (5 ml), and the mixture was stirred for 10 minutes under cooling with ice. The mixture was reacted for one hour at room temperature.

The reaction solution was distilled off under reduced pressure, and the crystal was filtered off.

The obtained crystal was washed twice with a small amount of ice-water, and dried to give the title compound (1.26 g) having the following physical data.

TLC : Rf 0.65 (ethyl acetate : acetic acid : water =6:2:1).

REFERENCE EXAMPLE 5 p-pivaloyloxybenzenesulfonyl chloride ##STR66##

Thionyl chloride (2.1 ml) was added to dimethylformamide solution (33 ml) of the compound (2.8 g) of Reference Example 4, and the mixture was stirred for 30 minutes under cooling with ice, and stirred for 30 minutes at room temperature.

The reaction solution was extracted with ether-hexane (1:1), and the extract was washed twice with ice-water.

The solution was dried with magnesium sulfate to give the title compound (2.49 g) having the following physical data.

TLC Rf 0.34 (hexane : ethyl acetate =10 : 1).

EXAMPLE 2 p-[N-((trans-p-carboxycyclohexyl)methyl)sulfamoyl]phenyl ester of pivalic acid ##STR67##

By using sulfonyl chloride of Reference Example 5, and by the same procedure of Reference Example 1, the title compound (110 mg) having the following physical data was obtained.

TLC : Rf 0.32 (chloroform : methanol : acetic acid=100:5:1);

NMR 7.9(2H,d), 7.25(2H,d), 4.4(1H,m), 2.8(2H,m), 2.4-1.0(9H,m), 1.35(9H,s).

Hereinafter, by using sulfonyl chloride of Reference Example 5 and corresponding amine, and by the same procedure of Example 2, the desired compounds described in the following Table IV and V were obtained.

    TABLE IV       ##STR68##            Example No.      ##STR69##       Name TLC IR (cm.sup.-1) or NMR        2(1)       ##STR70##       p-[N-(p-carboxymethylphenyl)sulfamoyl]phenyl ester of pivalicacid Rf    (      0.3chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD):δ 7.8(2H,d),7.4˜7.0(6H,m),3.55(2H,s),1.35(9H,s)  2(2)       ##STR71##       p-[N-(p-trans-2-carboxyvinyl)phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.33(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD):δ 8.0˜7.0(10H,m),6.2(1H,d),1.35(9H,s)  2(3)       ##STR72##       p-[N-(m-carboxyphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.31(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD):δ       7.85(2H,d),7.8˜7.65(2H,m),7.5˜7.3(3H,m),7.2˜7.0(2H,d)       2(4)      ##STR73##       p-[N-(p-carboxybenzyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.31(chloroform:methanol:acetic acid =100:5:1) δ       8.1˜7.8(4H,m),7.5˜7.2(5H,m),4.2(2H,s),1.35(9H,s)  2(5)      NHC(CH.sub.3).sub.3 p-(N-tert-butylsulfamoyl)phenyl ester Rf 0.65 ν      3260,2980,1740,  H of pivalic acid (methylene 1590,1480,1310,      chloride: 1200    ethyl acetate =    30:1)       2(6)      ##STR74##       p-[N-(p-acetoxyphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.58(ethyl acetate:hexane =1:1) ν       3260,2960,1750,1740,1590,1300,1470,1400,1340,1230,1190,1150,1100  2(7)       ##STR75##       p-[N-(p-hydroxyphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.08(methylenechloride:ethyl acetate =30:1) ν       1745,1590,1510,1400,1320,1270,1200       2(8)      ##STR76##       p-[N-(m-hydroxyphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.10(methylenechloride:ethyl acetate =30:1) ν       3400,3240,1640,1610,1600,1480       2(9)      ##STR77##       p-[N-(4-pyridyl)sulfamoyl]phenylester of pivalic acid Rf 0.30(chloroform      :methanol =10:1) ν 3500˜2300,1750,1630,1590,1490,1350  2(10)       ##STR78##       p-[N-(p-sulfamoylphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.18(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD):δ 7.9(2H,d),7.75(2H,d),7.3(2H,d),7.2(2H,d),1.35(9H,s)  2(11)       ##STR79##       p-[N-(p-carbamoylphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.22(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD):δ 7.85(2H,d),7.70(2H,d),7.18(2H,d),7.14(2H,d)       2(12)      ##STR80##       p-[N-(α-pyridylmethyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.75(chloroform:methanol: =10:1) ν 1750,1590,1480,1330,1200,1160      2(13)       ##STR81##       p-[N-(β -pyridylmethyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.57(chloroform:methanol: =10:1) ν 1750,1590,1480,1320,1200,1150,1100       2(14)      ##STR82##       p-[N-(4-pyridylmethyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.57(chloroform:methanol: =10:1) ν 1750,1600,1590,1480,1420,1320,1200       2(15)      ##STR83##       p-[N-(o-hydroxyphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.42(methylenechloride:ethyl acetate =10:1) ν       3450,3250,1730,1590,1480,1430       2(16)      ##STR84##       P-[(3-carboxy)piperidinosulfonyl]phenyl ester of pivalic acid Rf      0.41(chloroform:methanol:acetic acid =100:5:1) δ       7.8(2H,d),7.3(2H,d),4.0˜3.4(3H,b),3.0˜1.3(6H,b),1.35(9H,s)      2(17)       ##STR85##        2-methyl-4-(N-phenylsulfamoyl)phenyl ester of acetic acid Rf 0.44(hexan      e:ethyl acetate =5:2) δ       7.7˜7.5(2H,m),7.4˜7.0(6H,m),6.45(1H,bs),2.2(3H,s),1.35(9H,s)       2(18)      ##STR86##       2-methyl-4-[N-methyl-N-(o-carboxy)sulfamoyl]phenyl ester of pivalicacid R      f 0.43(chloroform:methanol:acetic acid =100:5:1) δ       7.9(1H,dd),7.7˜7.0(6H,m),3.35(3H,s),2.2(3H,s),1.4(9H,s)  2(19)       ##STR87##       2-methyl-4-[(2S-carboxy-1-pyrolidinyl)sulfonyl]phenyl ester ofpivalic      acid Rf 0.26(chloroform:methanol:acetic acid =100:5:1) δ       7.8(1H,s),7.75(1H,d),7.2(1H,d),4.4˜4.2(1H,m),2.4˜1.6(7H,m),1      .4(9H,m)       2(20)      ##STR88##       2-methyl-4-[N-(p-carboxycyclohexanemethyl)sulfamoyl]phenyl ester of      pivalic acid Rf 0.40(chloroform:methanol:acetic acid =100:5:1) δ      7.8(1H,s),7.75(1H,d),2.85(2H,d),2.3(3H,s),1.4(9H,s)       2(21)      ##STR89##       2-methyl-4-[(4-carboxy)piperidinosulfonyl]phenyl ester ofpivalic acid      Rf 0.36(chloroform:methanol:acetic acid =100:5:1) δ       7.65(1H,s),7.6(1H,d),3.8˜3.4(3H,b),2.7˜2.3(2H,m),2.25(3H,s),      2.2˜1.6(5H,b),1.4(9H,s)       2(22)      ##STR90##       2-methyl-4-[(3-carboxy)piperidinosulfonyl]phenyl ester ofpivalic acid      Rf 0.36(chloroform:methanol:acetic acid =100:5:1) δ                1       7.68(1H,s),7.61H,d),3.9˜3.3(2H,m),2.8˜2.4(3H,m),2.25(3H,s),1      .35(9H,s)       2(23)      ##STR91##       2-methyl-4-[(N-((o-methoxycarbonyl)phenyl)sulfamoyl]phenyl ester      ofpivalic acid Rf 0.6(methylene:chloride:ethyl acetate =30:1) ν      3125,2970,1740,1685,1600,1580,1490,1265,1110,940,760       2(24)      ##STR92##       2-methyl-4-[N-((o-acetyl)phenyl)sulfamoyl]phenyl ester of pivalicacid      Rf 0.6(methylene:chloride:ethyl acetate =30:1) ν       2980,1755,1640,1605,1580,1495,1450,1400,1260,1150,1105       2(25)      ##STR93##       2-methyl-4-[N-((o-aminocarbonyl)phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.1(methylenechloride:ethyl acetate =30:1) ν       3450,3200,2970,1730,1670,1615,1575,1490,1340,1280,1220,1150,1110  2(26)       ##STR94##       2-methyl-4-[(2-carboxy)piperidinosulfonyl]phenyl ester ofpivalic acid      Rf 0.41(chloroform:methanol:acetic acid =100:5:1) δ       7.7(1H,d),7.75(1H,s),7.1(1H,d),4.8(1H,b),3.8(1H,b),3.2(1H,b),2.2(3H,s),2      ˜1.2(6H,b),1.35(9H,s)       2(27)      ##STR95##       2-methyl-4-[N-(o-phenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.20(hexane: ethyl acetate =5:2) δ       7.5(2H,b),7.2˜6.5(5H,m),6.2(2H,b),2.1(3H,s),1.3(9H,s)  2(28)       ##STR96##       2-methyl-4-[N-(o-(N,N-dimethyl-carbamoylmethoxycarbonyl)phenyl)sulfamoyl      ]phenyl ester of pivalic acid Rf 0.51(chloroform:methanol:acetic acid      =100:5:1) ν 1760,1690,1680,1490,1590,1410,1260,1150,1110  2(29)      NH(CH.sub.2).sub.2       COOH 2-methyl-4-[(N-carboxyethyl) Rf 0.33 (CDCl.sub.3)  2-CH.sub.3      sulfamoyl]phenyl ester of pivalic (chloroform: δ 7.8(1H,s),7.75      acid methanol: (1H,d),7.15(1H,    acetic acid = d),5.7(1H,b),      100:5:1) 3.25(2H,m),2.6     (2H,t),2.25(3H,     s),1.35(9H,s)  2(30)       ##STR97##       2-methyl-4-[N-(o-carboxycyclo-pentyl)sulfamoyl]phenyl ester of pivalicac      id Rf 0.33(Chloroform:methanol =10:1) (CDCl.sub.3)δ       7.8(1H,s),7.75(1H,d),7.12(1H,d),4.0˜3.6(1H,b),2.25(3H,s),2.1.about      .1.6(6H,b),1.35(9H,s)       2(31)      ##STR98##       2-methyl-4-[N-(o-carboxycyclo-hexyl)sulfamoyl]phenyl ester of pivalicaci      d Rf 0.33(chloroform:methanol: =10:1) (CDCl.sub.3)δ       7.65˜7.90(2H,m),7.1(1H,d),2.25(3H,s),1.4(9H,s),1.0˜3.0(10H,m      )       2(32)      ##STR99##       2-methyl-4-[N-(2-methoxy-5-carboxy)sulfamoyl]phenyl ester of pivalicacid       Rf 0.33(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      8.18(1H,d),7.8(1H,d,d),7.6(1H,s),7.53(1H,d),6.95(1H,d),6.75(1H,d),3.65(3H      ,s),2.2(3H,s),1.35(9H,s)       2(33)      ##STR100##       2.6-dimethyl-4-[N-(p-tolyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.44(methylenechloride:ethyl acetate =30:1) ν       1750,1470,1390,1330,1280,1140,1100       2(34)      ##STR101##       4-[N-(o-hydroxymethylphenyl)sulfamoyl]phenyl ester of pivalicacid Rf      0.76(ethyl acetate:hexane =2:1) ν       3470,3050,2950,2850,1750,1590,1470,1320,1210       2(35)      ##STR102##       2-methyl-4-[N-(trans-o-carboxy-cyclopentyl)sulfamoyl]phenyl ester      ofpivalic acid Rf 0.33(chloroform:methanol: =10:1) (CDCl.sub.3)δ      7.75(1H,s),7.7(1H,d),7.1(1H,d),3.75(1H,m),2.5(1H,m),2.25(3H,s),2.4˜      1.4(6H,m),1.4(9H,s)       2(36)      ##STR103##       2-methyl-4-[N-(cis-o-carboxyl-cyclopentyl)sulfamoyl]phenyl ester      ofpivalic acid Rf 0.33(chloroform:methanol =10:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.75(1H,s),7.7(1H,d),7.1(1H,d),3.75(1H,m),2.8(1H,m),2.25(3H,s),2.0.about      .1.4(6H,m),1.4(9H,s)       2(37)      ##STR104##       2-methyl-4-[N-cis-o-carboxy-cyclohexyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.18 (chloroform:methanol: =10:1) ν       3260,2400˜2700,1740,1700,1470,1420,1330       2(38)      ##STR105##       2-methyl-4-[N-(o-(N,N-diethyl-carbamoylmethoxycarbonyl)phenyl)sulfamoyl]      phenyl ester of pivalicacid Rf 0.55(methylenechloride:ethyl acetate      =30:1) ν 3160,3000,1755,1670,1590,1490,1270,1100,940       2(39)      ##STR106##       2-methyl-4-[N-(o-sulfamoylphenyl)sulfamoyl]phenyl ester of pivalicacid      Rf 0.20(chloroform:methanol:acetic acid =100:5:1) ν       1750,1720,1590,1570,1460       2(40)      ##STR107##       2-methyl-4-[N-(m-carboxyphenyl)sulfamoyl]phenyl ester of pivalicacid Rf      0.33(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.75˜7.4(3H,m),7.4˜7.1(3H,m), 6.97(1H,d),2.15(3H,s),1.35(9H,      s)       2(41)      ##STR108##       4-[N-(m-carboxymethylphenyl)sulfamoyl]phenyl ester of pivalicacid Rf      0.33(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ 7.7(2H,d),7.2˜6.8(6H,m),3.45(2H,s),1.30(9H,s)  2(42)       ##STR109##       2-methyl-4-[N-(m-carboxymethyl-phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.31(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.55(1H,s),7.5(1H,d),7.2˜6.8(5H,m),3.45(2H,s),2.15(3H,s),1.35(9H,s      )       2(43)      ##STR110##       2-methyl-4-[N-(m-carboxyethylphenyl)sulfamoyl]phenyl ester of pivalicaci      d Rf 0.31(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.62(1H,s),7.5 (1H,d),7.25˜6.9(4H,m),6.75(1H,b),6.6(1H,b),2.8(2H,t)      ,2.6(2H,t),2.2(3H,s),1.3 5(9H,s)       2(44)      ##STR111##       2-methyl-4-[N-(2-chloro-5-carboxyphenyl)sulfamoyl]phenyl esterof      pivalic acid Rf 0.34(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.      3 + CD.sub.3 OD)δ       8.2(1H,b),7.8˜7.45(3H,b),7.3(1H,d),7.0(1H,d),2.2(3H,s),1.35(9H,s)       2(45)      ##STR112##       4-[N-(m-carboxyethylphenyl)sulfamoyl]phenyl ester of pivalic acid Rf      0.27(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.65(2H,d),7.1(2H,d),7.35˜6.8(2H,m),6.8˜6.6(2H,d),2.85(2H,t),      2.55(2H,t),1.35(9H,s)       2(46)      ##STR113##       2-methyl-4-[N-(m-sulfonyl)sulfamoyl]phenyl ester of pivalic acid Rf     (      0.35chloroform:methanol:acetic acid =10:3:1) (CD.sub.3       SOCD.sub.3)δ       7.7˜7.6(2H,m),7.4˜6.9(5H,m),2.15(3H,s),1.30(9H,s)  2(47)       ##STR114##       2-methyl-4-[N-(2-sulfo-4-methyl-phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.44(chloroform:methanol:acetic acid =10:3:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.9˜7.5(3H,m),7.5˜6.9(3H,m),2.3(3H,s),2.2(3H,s),1.35(9H,s)      2(48)       ##STR115##       2-methyl-4-[N-(m-carboxymethoxyphenyl)sulfamoyl]phenyl ester of pivalic      acid Rf 0.39(chloroform:methanol:acetic acid =30:3:1) (CDCl.sub.3)δ       7.55(1H,s),7.5(1H,d),7.32˜6.5(5H,m),6.2(1H,bs),4.45(2H,s),2.2(3H,s)      ,1.37(9H,s)       2(49)      ##STR116##       2-methyl-4-[N-(1,4-dioxa-2-carboxy-8-yl-naphthalene)sulfamoyl]phenyl      ester of pivalic acid Rf 0.27(chloroform:methanol:acetic acid =30:3:1)      (CDCl.sub.3)δ       7.6(1H,s),7.5(1H,d),7.35(1H,d),7.2(1H,d,d),6.9(1H,d),6.85(1H,d),4.7(1H,s      ),4.5(1H,d),4.1(1H, d,d),2.1(1H,s),1.38(1H,s)       2(50)      ##STR117##       N-[m-(3-methyl-4-pivaloyloxy-benzene)sulfonylaminobenzoyl]glycine Rf      0.26(chloroform:methanol:acetic acid =30:3:1) (CDCl.sub.3 + CD.sub.3      OD)δ 7.6˜6.9(7H,m),4.1(2H,s),2.15(3H,s),1.35(9H,s)  2(51)       ##STR118##       2-methyl-4-[N-(o-carboxypropoxy-phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.45(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ                                                      (       7.6˜7.3(3H,m),7.1˜6.5(4H,m),3.8(2H,t),2.42H,t),2.15(3H,s),2.      02(2H,q), 1.35(9H,s)       2(52)      ##STR119##       2-methyl-4-[N-(3,5-dicarboxyphenyl)sulfamoyl]phenyl ester of pivalicacid       Rf 0.39(chloroform:methanol:acetic acid =30:3:1) (CDCl.sub.3 + CD.sub.3      OD)δ       8.38(1H,t),7.98(2H,s),7.8˜7.6(2H,m),7.06(1H,d),2.2(3H,s),1.38(9H,s      )

    TABLE IV            2(53)       ##STR120##       N-[o-(3-methyl-4-pivaloyloxy-benzene)sulfonylaminobenzoyl]glycine Rf      0.41(chloroform:methanol:acetic acid =30:3:1) ν       2970,1740,1630,1600,1520,1480,1390,1330,1260,1230,1150,1090,930,760,590       2(54)      ##STR121##       2-methyl-4-[N-(1,4-dioxa-2-tetrazolyl-8-yl-naphthalene)sulfamoyl]phenyl      ester of pivalicacid Rf 0.46(chloroform:methanol:acetic acid =30:3:1)      (CDCl.sub.3)δ       7.6(1H,s),7.5(1H,d),7.3˜6.7(4H,m),5.2(1H,fou),4.5(2H,eig),2.1(3H,s      ),1.4(9H,s)       2(55)      ##STR122##       N-[o-(3-methyl-4-pivaloyloxy-benzene)sulfonylaminobenzoyl]-L-valine Rf      0.44(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.80(1H,d),7.32˜7.2(4H,m),7.15(1H,t),7.0(1H,d),6.4(1H,d),4.5(1H,q),      2.3(1H,m),2.1(3H,s),1.35(9H,s)       2(56)      ##STR123##       N-[5-chloro-2-(3-methyl-4-pivaloyloxybenzene)sulfonylamino-benzoyl]glyci      ne Rf 0.29(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ 7.8˜6.9(7H,m),3.95(2H,s),2.15(3H,s),1.35(9H,s)       2(57)      ##STR124##       N-[o-(3-methyl-4-pivaloyloxy-benzene)sulfonylaminobenzoyl]-dl-alanine      Rf 0.24(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.75(1H,d),7.6(1H,s),7.65˜7.4(2H,m),7.3˜7.05(2H,m),7.0(1H,d),      6.55(1H,d),4.6(1H,q),2.1(3H,s),2.5(3H,d),1.35(9H,s)       2(58)      ##STR125##       N-[o-(3-methyl-4-pivaloyloxy-benzene)sulfonylaminobenzoyl]-β-alanin      e Rf 0.36(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.75(1H,d),7.6(1H,s),7.55˜7.2(3H,m),7.1(1H,t),6.95(1H,d),6.6(1H,b),      3.5(2H,q),2.6(2H,q),2.1(3H,s),1.35(9H,s)       2(59)      ##STR126##       2-methyl-4-[N-(2-benzyloxycarbonyl-5-nitrophenyl)sulfamoyl]phenyl ester      ofpivalic acid Rf 0.27(ethyl acetate:hexane =1:5) (CDCl.sub.3)δ      8.5(1H,d),8.1(1H,d),7.75(3H,m),7.4(5H,s),7.1(1H,d),5.4(2H,s)  2(60)       ##STR127##       N-[2-((3-methyl-4-pivaloyloxybenzene)sulfonylamino)-5-penthyloxybenzoyl]g      lycine Rf 0.22(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3      OD)δ       7.3˜7.6(3H,m),6.9˜7.2(3H,m),3.95(2H,t),3.9(2H,s),2.15(3H,s),       2(61)      ##STR128##       N-[5-decyloxy-2-(3-methyl-4-pivaloyloxybenzene)sulfonylamino-benzoyl]gly      cine Rf 0.25(ethyl acetate:hexane:acetic acid =100:10:0.5) (CD.sub.3      OD)δ       7.35˜7.6(3H,m)6.9˜7.2(2H,m),3.95(2H,t),3.9(2H,s),2.1(3H,s)      2(62)       ##STR129##       2-methyl-4-[N-(2-prolylcarbonylphenyl)sulfamoyl]phenyl ester of pivalic      acid Rf 0.18(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3).delta      .       8.65(1H,s),7.8˜7.6(3H,m),7.4˜7.0(5H,m),4.6(1H,m),3.25(2H,t),2      .3˜2.1(2H,m),2.15(3H,s),2.0˜1.7(2H,m),1.35 (9H,s)  2(63)       ##STR130##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine Rf 0.14(chlorofo      rm:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub. 3 OD)δ      7.8˜7.0(8H,m),3.95(2H,s),1.30(9H,s)       2(64)      ##STR131##       N-[2-(3-methyl-4-pivaloyloxybenzene)sulfonylamino-5-methylbenzoyl]glycin      e Rf 0.20(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.7˜6.8(6H,m),6.3(1H,b),4.0(2H,d),2.3(3H,s),2.1(3H,s),1.3(9H,s)      2(65)       ##STR132##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-l-alanine Rf      0.24(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.8˜6.9(7H,m),6.5(1H,b),4.6(1H,b),2.1(3H,s),1.45(3H,d),1.35(9H,s)      2(66)       ##STR133##       N-[5-chloro-2-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-l-ala      nine Rf 0.3(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.      3)δ                                                                4       7.75(1H,d),7.55(1H,s),7.5˜7.3(3H,m),6.95(1H,d),6.4(1H,b),.55(1H,m)      ,2.15(3H,s),1.45(3H,d),1.35(9H,s)       2(67)      ##STR134##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-phenyalanine       Rf 0.30(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3       OD)δ       6.95˜7.7(12H,m),4.6˜4.8(1H,m),3.0˜3.4(2H,m),2.1(3H,s),1      .35(9H,s)       2(68)      ##STR135##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-dl-methionine R      f 0.29(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3 OD)δ 7      .55˜7.8(4H,m),7.45(1H,t),7.0˜7.2(2H,m),4.6˜4.7(1H,m),2.      4˜2.6(2H,m),2.13(3H,s),2.10(3H,s),2.0˜2.3(2H,m),1.35(9H,s)      2(69)       ##STR136##        N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-lysin.hydro      chloride Rf 0.73(ethyl acetate:acetic acid:water =3:1:0.5) (CD.sub.3      OD)δ       7.57˜7.80(3H,m),7.35˜7.55(2H,m),7.0˜7.22(2H,m),4.45.ab      out.4.65(1H,m),2.95(2H,t),2.15(3H,s),1.4˜2.1(6H,m), 1.35(9H,s)      2(70)       ##STR137##       2-methyl-4-[N-(2-(N-carboxyphenyl-3-yl)carbamoylphenyl)sulfamoyl]phenyl      ester of pivalic acid Rf 0.52(ethyl acetate:hexane:acetic acid =10:10:0.5      ) ν 1750,1690,1540,1480,1330,1300,1230,1150,1110       2(71)      ##STR138##       2-methyl-4-[N-(2-carboxymethoxy-phenyl)sulfamoyl]phenyl ester ofpivalic      acid Rf 0.21(chloroform:methanol:acetic acid =30:3:1) (CDCl.sub.3)δ       7.7˜6.6(8H,m),4.5(2H,s),2.15(3H,s),1.3(9H,s)       2(72)      ##STR139##       N-[5-chloro-2-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-.beta      .-alanine Rf 0.28(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3).      delta.       7.8˜7.2(5H,m),7.0(1H,d),7.6(1H,b),3.6(2H,q),2.64(2H,t),2.2(3H,s),1      .35(9H,s)       2(73)      ##STR140##       2-methyl-4-[N-((2-carboxypropylcarbamoyl-4-chloro)phenyl)sulfamoyl]pheny      l ester of pivalic acid Rf 0.28(chloroform:methanol:acetic acid =100:5:1)       (CDCl.sub.3)δ       7.8˜7.2(5H,m),7.0(1H,d),6.4(1H,b),3.3(2H,q),2.5(2H,t),2.15(3H,s),1      .9(2H,m),1.35(9H,s)       2(74)      ##STR141##       2-methyl-4-[N-(2-(N-carboxyphenyl-4-yl)carbamoylphenyl)sulfamoyl]phenyl      ester of pivalic acid Rf 0.54(ethyl acetate:hexane:acetic acid =10:10:0.5      ) ν 1750,1680,1650,1590,1520,1480,1400,1320,1280,1250,1220  2(75)       ##STR142##       N-[2-(p-pivaloyloxybenzene)sulfonylamino-5-chlorobenzoyl]glycine Rf     (      0.23chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.7(2H,d),7.8˜7.6(1H,m),7.5˜7.4(2H,m),7.08(2H,d),6.3(1H,b),4.      08(2H,d),1.35(9H,s)       2(76)      ##STR143##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]tyrosine Rf      0.27(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD3OD)δ      7.32˜7.7(5H,m),7.0˜7.2(2H,m),7.05(2H,d),6.7(2H,d),2.6˜2      .75(1H,m),2.87˜4.25(2H,m),2.12(3H,s),1.35(9H,s)       2(77)      ##STR144##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminophenylacetyl]glycine      Rf 0.44(ethyl acetate:acetic acid =25:1) (CD.sub.3 OD)δ       7.5˜7.7(2H,m),7.0˜7.35(5H,m),3.9(2H,2),3.37(2H,s),2.2(3H,s),1      .41(9H,s)       2(78)      ##STR145##       N-[o-(4-pivaloyloxybenzene)sulfonylaminophenylacetyl]glycine Rf      0.37(ethyl acetate:acetic acid =25:1) ν 1750,1610,1530,1480,1400      2(79)       ##STR146##       4-[N-((2-carboxypropylcarbamoyl-4-chloro)phenyl)sulfamoyl]phenyl      esterof pivalic acid Rf 0.47(chloroform:methanol:acetic acid =100:5:1)      (CDCl.sub.3 + CD.sub.3 OD)δ       7.7(2H,d),7.5(1H,s),7.4˜7.2(2H,m),7.1(2H,d),3.2(2H,t),2.3(2H,t),1.      8(2H,m),1.3(9H,s)       2(80)      ##STR147##       N-[5-methylthio-2-(p-pivaloyloxy-benezene)sulfonylaminobenzoyl]glycine      Rf 0.34(chloroform:methanol:acetic acid =30:3:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.7(2H,d),7.6(1H,d),7.4˜7.2(2H,m),7.1(2H,d),3.98(2H,s),2.5(3H,s),1      .4(9H,s)        2(81)      ##STR148##       N-[2-(3-methyl-4-pivaloyloxybenzene)sulfonylamino-4-trifluoromethylbenzo      yl]glycine Rf 0.12(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3       OD)δ       7.92(1H,s),7.80(1H,d),7.55˜7.7(2H,m),7.45(1H,d),7.11(1H,d),4.0(2H,      s),2.16(3H,s)1.36(9H,s)       2(82)      ##STR149##       N-[2-(p-pivaloyloxybenzene)sulfonylamino-4-trifluoromethylbenzoyl]glycin      e Rf 0.12 (ethyl acetate:hexaneacetic acid =10:10:0.5) (CD.sub.3      OD)δ       7.95(1H,s),7.77(2H,d),7.80(1H,d),7.45(1H,d),7.20(2H,d),4.0(2H,s),1.33(9H      ,s)       2(83)      ##STR150##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-S-methyl-L-cysteine Rf      0.27(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ                                                               3       7.8(2H,d),7.7˜7.2(3H,m),7.1(2H,d),7.11(1H,d),4.8(1H,m),.05(2H,m),2      .15(3H,s),1.3(9H,s)       2(84)      ##STR151##       N-[2-(4-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-methionine Rf      0.34(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.8(2H,d),7.7˜7.2(3H,m),7.1(2H,d),7.11(1H,d),4.7(1H,m),2.8˜2      .0(4H,m),2.14(3H,s),1.3(9H,s)       2(85)      ##STR152##       N-[5-decyloxy-2-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine Rf      0.49(ethyl acetate:hexane:acetic acid =10:10:0.5) ν       3449,2926,1762,1728,1645,1607,1530,1501,1252       2(86)      ##STR153##       N-[2-(3-methyl-4-pivaloyloxybenzene)sulfonylamino-5-methylthiobenzoyl]gl      ycine Rf 0.25(chloroform:methanol:acetic acid = 100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.7˜7.2(5H,m),6.95(1H,d),2.95(2H,s),2.5(3H,s),2.2(3H,s),1.35(9H,s)       2(87)      ##STR154##       N-[2-(p-pivaloyloxybenzene)sulfonylamino-5-propylthiobenzoyl]glycine Rf      0.29(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.75(2H,d),7.6˜7.1(3H,m),7.1(2H,d),4.0(2H,s),2.9(2H,t),1.8˜1      .5(2H,m),1.35(9H,s),1.0(3H,t)       2(88)      ##STR155##       N-[o-(pivaloyloxybenezene)sulfonylaminobenzoyl]-2R-phenylglycine Rf     (      0.19ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3 OD)δ      7.55˜7.7(4H,m),7.2˜7.7(6H,m),7.15(1H,t),6.97(2H,d),5.57(1H,s)      ,1.3(9H,s)       2(89)      ##STR156##       N-[o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyl]-2R-phenylglyci      ne Rf 0.2(ethyl acetate:hexane:acetic acid =10:10:0.5) (CD.sub.3      OD)δ 7.2˜       7.8(10H,m),7.12(1H,t),6.90(1H,d),5.57(1H,s),2.06(3H,s),1.35(9H,s)      2(90)       ##STR157##       N-[5-methyl-2-(p-pivaloyloxybenzene)sulfonylamino-benzoyl]glycine Rf      0.27(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.7(2H,d),7.5(1H,s),7.3˜7.1(2H,b),7.0(2H,d),3.95(2H,s),2.3(3H,s),1      .3(9H,s)       2(91)      ##STR158##       4-[N-(o-(N-carboxyphenyl-3-yl)carbamoylphenyl)sulfamoyl]phenylester of      pivalic acid Rf 0.32(chloroform:methanol:acetic acid =100:5:1) ν      1752,1692,1646,1595,1554,1491,1409,1338,1304,1259,1209       2(92)      ##STR159##       N-[2-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine methylester Rf      0.77(chloroform:methanol: =10:1) (CDCl.sub.3)δ       7.7(2H,d),7.65(1H,b),7.55˜7.3(2H,m),7.2˜7.0(1H,m),7.0(2H,d),4      .0(2H,d),3.8(3H,s),1.35(9H,s)       2(93)      ##STR160##       2-[N-(2-(4-pivaloyloxybenzene)sulfonylaminobenzoyl)glycyloxy]-N,N-dimeth      ylacetamide Rf 0.53(chloroform:methanol =10:1) (CDCl.sub.3)δ      7.7(2H,d),7.8˜7.6(1H,b),7.55˜7.2(2H,m),7.2˜7.0(1H,m),7.      05(2H,d),4.8(2H,s),4.2(2H,d),3.0(6H,s),1.35(9H,s)       2(94)      ##STR161##       N-[5-pentyloxy-2-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine Rf      0.26(ethyl acetate:hexane:acetic acid =10:10:0.5) (CDCl.sub.3)δ      7.65(2H,d),7.50(1H,d),7.18(2H,d),7.11(1H,s),7.02(1H,dd),3.95(2H,t),3.88(2      H,s),1.65˜1.85(2H,m),1.25˜1.55(4H,m),1.33(9H,s),1.92(3H,t)      2(95)       ##STR162##       2-methyl-4-[N-((2-benzyloxy-carbonyl-4-chloro)phenyl)sulfamoyl]phenylest      er of pivalic acid Rf 0.30(ethyl acetate:hexane: =1:10)

    TABLE IV            2(96)       ##STR163##       2-methyl-4-[N-((2-benzyloxy-carbonyl-4-methyl)phenyl)sulfamoyl]phenylest      er of pivalic acid Rf 0.28(ethyl acetate:hexane: =1:10)       2(97)      ##STR164##       2-isopropyl-4-[N-(o-benzyloxycarbonylphenyl)sulfamoyl]phenyl ester of      pivalic acid Rf 0.32(ethyl acetate:hexane: =1:10)       2(98)      ##STR165##       2-isopropyl-4-[N-((2-benzyloxycarbonyl-4-chloro)phenyl)sulfamoyl]phenyl      ester of pivalicacid Rf 0.35(ethyl acetate:hexane: =1:10)  2(99)       ##STR166##       2-methyl-4-[N-(2-benzyloxycarbonyl-phenyl)sulfamoyl]phenyl ester      ofpivalic acid Rf 0.58(ethyl acetate:hexane: =1:10)       2(100)      ##STR167##       2-methyl-4-[N-(2,5-dibenzyloxy-carbonylphenyl)sulfamoyl]phenyl esterof      pivalic acid Rf 0.12(ethyl acetate:hexane: =1:10)       2(101)      ##STR168##       2-methyl-4-[N-(3-benzyloxycarbonylphenyl)sulfamoyl]phenyl ester of      pivalic acid Rf 0.37(ethyl acetate:hexane: =2:5)       2(102)      ##STR169##       2-methyl-4-[N-(2-benzoyloxycarbonyl-4-hydroxy)phenyl)sulfamoyl]phenyl      ester of pivalic acid Rf 0.18(methylenechloride:methanol =10:1)   2(103)       ##STR170##       2,6-dimethyl-4-[N-(o-benzyloxycarbonylphenyl)sulfamoyl]phenyl ester of      pivalic acid       2(104)      ##STR171##       2-methyl-4-[N-((4-acetyloxy-2-benzyloxycarbonyl)phenyl)sulfamoyl]phenyl      ester of pivalic acid Rf 0.39(chloroform:methanol =10:1)  2(105)       ##STR172##       2-methyl-4-[N-((2-benzyloxycarbonyl-4-hexanoyloxy)phenyl)sulfamoyl]pheny      l ester of pivalic acid Rf 0.44(mchloroform:methanol =10:1)  2(106)       ##STR173##       2-methyl-4-[N-(2,6-dibenzyloxy-carbonylphenyl)sulfamoyl]phenyl esterof      pivalic acid Rf 0.12(hexane:ethyl acetate =10:1)       2(107)      ##STR174##       o-(3-methyl-4-pivaloyloxybenzene)sulfonylaminobenzoyloxy acetic      acidbenzylester Rf 0.41(hexane:ethyl acetate =5:2)       2(114)      ##STR175##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-2S-phenylglycine Rf      0.31(ethyl acetate:hexane:acetic acid =10:10:0.5) ν       1751,1641,1594,1520,1493,1456,1398,1340,1275,1207,1164,1104  2(115)       ##STR176##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-leucine Rf 0.45(Chlor      oform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ       7.75(2H,d),7.85˜7.60(1H,m),7.6˜7.15(3H,m),7.05(2H,d),6.40(1H      ,b),5.4(1H,b),4.6(1H,m),2.0˜1.4(3H,b),1.35(9H,s),1.0(6H,d)      2(116)       ##STR177##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycinamide Rf 0.28(chlo      roform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3 OD +      CD.sub.3 SOCD.sub.3)δ       7.75(2H,d),7.65˜7.35(3H,m),7.1(2H,d),7.2˜7.0(1H,b),3.95(2H,s      ),1.35(9H,s)       2(117)      ##STR178##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-alanine Rf 0.28(chlor      oform:methanolacetic acid =100:5:1) (CDCl.sub.3)δ       7.75(2H,d),7.8˜7.7(1H,b),7.5˜7.4(2H,m),7.05(2H,d),7.2˜7      .1(1H,m),6.5(1H,d),4.6(1H,q),1.5(3H,d),1.35(9H,s)       2(118)      ##STR179##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-β-alanine Rf      0.48(Chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.7(2H,d), 7.8˜7.7(1H,b),7.45(1H,t),7.3(1H,d),7.2(1H,t),7.1(1H,d),7      .05(2H,d),6.6(1H,b),3.5(2H,q),2.6(2H,t),1.35(9H,s)       2(119)      ##STR180##       p-[N-(o-carboxyethoxyphenyl)sulfamoyl]phenyl ester of pivalicacid Rf      0.36(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.7(2H,d),7.75˜7.65(1H,b),7.2˜7.0(5H,m),6.8(1H,d),4.0(2H,t),2      .6(2H,t),1.35(9H,s)       2(120)      ##STR181##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-S-valine Rf 0.34(acetic       acid:chloroform =1:19) ν 2972,1752,1640,1595,1527,1492,1398  2(121)       ##STR182##       p-[N-(o-carboxypropoxyphenyl)sulfamoyl]phenyl ester of pivalicacid Rf      0.48(Chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.7(2H,d), 7.45(1H,d,d),7.0(2H,d),7.1˜6.5(5H,m),3.8(2H,t),2.4(2H,t)      ,2.0(2H,b),1.35(9H,s)       2(122)      ##STR183##       N-methyl-N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]glycine Rf     (      0.17chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3 OD      + D.sub.2 O)δ       7.8(2H,d),7.8˜7.5(1H,b),7.1(2H,d),7.4˜7.0(4H,m),4.1(2H,s),2.      7(3H,s),1.35(9H,s)       2(123)      ##STR184##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-phenylalanine Rf     (      0.36chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.7(2H,d),7.6(1H,d),7.05(2H,d),7.4˜6.8(8H,m),4.8(1H,b),3.2(2H,m),1      .35(9H,s)       2(124)      ##STR185##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-D-phenylalanine Rf     (      0.36Chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.7(2H,d),7.6(1H,d),7.05(2H,d),7.4˜6.8(8H,m),4.8(1H,b),3.2(2H,m),1      .35(9H,s)       2(125)      ##STR186##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-L-tryptophan Rf      0.25(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ                                                               3       7.75(2H,d),7.6(1H,d),7.0(2H,d),7.6˜6.8(8H,m),4.85(1H,b),.35(2H,d),1      .35(9H,s)       2(126)      ##STR187##       N-[o-(N-methyl-N-(p-pivaloyloxybenzene)sulfonylaminobenzoyl)]glycine Rf      0.46(chloroform:methanol:THF =30:3:1) ν                               1       3391,2977,1756,1662,1597,1535,482,1405       2(127)      ##STR188##       dl-3-phenyl-3-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]amino      propionicacid Rf 0.5(Chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.      3 + CD.sub.3 OD)δ       7.6(2H,d),7.7˜7.5(1H,m),7.5˜7.1(7H,m),7.0(1H,d,d),6.9(2H,d),5      .5(1H,b ),2.9(2H,d),1.135(9H,s)       2(128)      ##STR189##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-4-piperidinecarboxylic      acid Rf 0.5(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.7(1H,d),7.6˜7.4(1H,m),7.4˜7.2(1H,m),7.2˜6.9(4H,m),4.      0˜3.6(1H,b),2.9˜2.4(4H,b),2.0˜1.4(4H,b) , 1.35(9H,s)      2(129)       ##STR190##       N-[ o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-D-methionine Rf      0.45(chloroform:methanolacetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3      OD)δ       7.8(2H,d),7.7˜7.1(4H,m),7.1(2H,d),4.7(1H,b),2.9(3H,s),2.6˜1.      9(4H,m),1.35(9H,s)       2(130)      ##STR191##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-D-valine Rf 0.46(ethyl      acetate:n-hexane:acetic acid =10:10:0.5) ν       3392,2973,1746,1641,1595,1528,1493,1398       2(131)      ##STR192##       p-[N-(o-carboxypropylcarbamoylphenyl)sulfamoyl]phenyl ester of pivalicac      id Rf 0.36(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.7(2H,d),7.7˜7.5(1H,b),7.4˜7.2(2H,m),7.0(2H,d),7.1(1H,d),3.      3(2H,t),2.4(2H,t ),1.9(2H,q),1.35(9H,s)       2(132)      ##STR193##       p-[N-(o-carboxyheptylcarbamoylphenyl)sulfamoyl]phenyl ester of pivalicac      id Rf 0.38(chloroform:methanolacetic acid =100:5:1) (CDCl.sub.3 +      CD.sub.3 OD)δ       7.7(2H,d),7.7˜7.6(1H,b),7.4˜7.2(2H,m),7.0(2H,d),7.1(1H,b),3.      2(2H,b),2.3(2H,b) ,1.9˜1.2(6H,b),1.35(9H,s)       2(133)      ##STR194##       N-[o-(p-pivaloyloxybenzene)sulfonylaminobenzoyl]-D-alanine Rf 0.28(chlor      oform:methanolacetic acid =100:5:1) (CDCl.sub.3 + CD.sub.3 OD))δ      7.75(2H,d),7.8˜7.7(1H,b),7.5˜7.4(2H,m),7.05(2H,d),7.2˜7      .1(1H,m),4.6(1H,m),1.5(3H,d),1.35(9H,s)       2(134)      ##STR195##       N-[(p-pivaloyloxybenzene)sulfonyl]-4-piperidine carboxylic acid Rf      0.4(chloroform:methanol:acetic acid =100:5:1) (CDCl.sub.3)δ      7.75(2H,d),7.2(2H,d),3.6(2H,b),2.7˜2.0(3H,m),2.0˜1.6(4H,m),1.      20(9H,s)       2(135)      ##STR196##       4-[(p-pivaloyloxybenzene)sulfonylamino]-2-naphtoic acid Rf 0.4(chlorofor      m:methanolacetic acid =100:5:1) (CDCl.sub.3)δ       8.9(1H,d),8.1(1H,d),7.75(2H,d),8.0˜7.8(1H,b),7.6˜7.3(3H,m),7      .0(2H,d),1.35(9H,s)      *The number of the carbon atoms of benzene ring were named from a carbon      atom combined with the oxygen atom in pivaloyl group as first.

                                      TABLE V                                      __________________________________________________________________________      ##STR197##                                                                     No.Example                                                                          ##STR198##      Name              TLC    or NMRIR                        __________________________________________________________________________                                                   (cm.sup.-1)                       2(108)                                                                              ##STR199##     2-chloro-4-[N-(p-tolyl)carbamoyl] phenyl ester of                              pivalic acid      Rf 0.77 (methylene chloride:                                                   acetic acid = 30:1)                                                                   (CDCl.sub.3) δ                                                           7.5(2H,b), 7.2˜6.5(5H,                                                   m), 6.2(2H,b), 2.1(3H,s),                                                      1.3(9H,s)                         2(109)                                                                              ##STR200##     2-methoxy-p-[N-(p-tolyl)carbamoyl] phenyl ester of                             pivalic acid      Rf 0.74 (methylene chloride:                                                   acetic acid = 30:1)                                                                   ν 3200,2980,1750,                                                           1640,1600,1510, 1400,1330,12                                                   80, 1110                          2(110)                                                                              ##STR201##     4-[N-(o-benzyloxycarbonylphenyl) carbamoyl]phenyl                              ester of pivalic acid                                                                            Rf 0.83 (methylene chloride:                                                   acetic acid = 30:1)                      2(111)                                                                              ##STR202##     4-[N-(2-pyridyl)carbamoyl]phenyl ester of pivalic                              acid              Rf 0.30 (chloroform: methanol =                                                10:1)                                    2(112)                                                                              ##STR203##     3-acetyloxy-4-[(N-methyl-N-phenyl) carbamoyl]phenyl                            ester of pivalic acid                                                                            Rf 0.24 (methylene chloride:                                                   acetic acid = 30:1)                                                                   (CHDl.sub.3) δ                                                           7.1˜7.5(6H,m),                                                           6.7˜7.0(2H,m),                                                           3.5(3H,s), 2.3(3H,s),                                                          1.3(9H,s)                         2(113)                                                                              ##STR204##     4-[N-(m-benzyloxycarbonylphenyl) carbamoyl]phenyl                              ester of pivalic acid                                                                            Rf 0.38 (methylene chloride:                                                   acetic acid = 30:1)                     __________________________________________________________________________

EXAMPLE 3 p-[N-(p-(p-guanidinobenzoyloxy)phenyl)sulfamoyl]phenyl ester of pivalic acid ##STR205##

p-Guanidinobenzoyl chloride hydrochloride (800 mg) was added to pyridine solution (5 ml) of the compound of the present invention (500 mg) obtained in Example 2(7) under cooling with ice, and the mixture was stirred for 2 hours.

After reaction, ether was added to the reaction mixture and the supernatant was decanted. Saturated aqueous solution of sodium bicarbonate was added to the residue to obtain oily carbonate.

Further, the supernatant was decanted and the residue was purified by column chromatography on silica-gel (ethyl acetate : acetic acid : water =400 : 100 : 30) to give the title compound (532 mg) having the following physical data.

TLC : Rf 0.80 (ethyl acetate: acetic acid : water=3:1:1);

IR:ν3600˜2300, 1750˜1700, 1680, 1500, 1400.

EXAMPLE 4 p-[N-(p-benzyloxycarbonylphenyl)sulfamoyl]phenyl ester of pivalic acid ##STR206##

The title compound (210 mg, same as compound obtained in Example 1(5) was obtained by the same procedure as Reference Example 1→Example 1, by using a corresponding sulfonylchloride compound as starting material.

The compounds of the present invention were obtained by the same procedure as Example 4, by using a corresponding amine and pivaloyl chloride.

                                      TABLE VI                                     __________________________________________________________________________      ##STR207##                                                                     No.Example                                                                          ##STR208##        Name              TLC     or NMRIR                     __________________________________________________________________________                                                      (cm.sup.-1)                   4(1)                                                                                 ##STR209##       p-[N-((1-benzyloxycarbonyl-1-benzyl) methyl)sulfamo                            yl]phenyl ester of pivalic acid                                                                  Rf 0.47 (hexane: ethyl acetate =                                               :2)                                   4(2)                                                                                 ##STR210##       p-[N-((1-benzyloxycarbonyl-1-phenyl) methyl)sulfamo                            yl]phenyl ester of  pivalic acid                                                                 Rf 0.40 (hexane: ethyl acetate =                                               :2)                                   4(3)                                                                                 ##STR211##       p-[N-((o-benzyloxycarbonyl)phenyl) sulfamoyl]phenyl                             ester of pivalic acid                                                                           Rf 0.62 (hexane: ethyl acetate =                                               :2)                                   4(4)                                                                                 ##STR212##       2-methyl-4-[N-((o-benzyloxycarbonyl) phenyl)sulfamo                            yl]phenyl ester of pivalic acid                                                                  Rf 0.62 (hexane: ethyl acetate =                                               :2)                                   4(5)                                                                                 ##STR213##       p-(N-phenethylsulfamoyl)phenyl ester of pivalic                                acid              Rf 0.41 (hexane: ethyl acetate =                                               :2)     δ 7.85(2H,d),                                                            7.4˜7.0(7H,m),                                                           4.5˜4.2(1H,b),                                                           3.4˜3.1(2H,m),                                                           2.8(2H,t), 1.35(9H,s)         4(6)                                                                                 ##STR214##       p-(N-benzylsulfamoyl)phenyl ester of pivalic                                                     Rf 0.47  (hexane: ethyl acetate                                                = 5:2)  δ 7.9(2H,d),                                                             7.4˜7.2(7H,m),                                                           4.7(1H,b), 4.2(2H,d),                                                          1.35(9H,s)                    __________________________________________________________________________

EXAMPLE 5 p-[N-(p-carboxyphenyl)sulfamoyl]phenyl ester of pivalic acid ##STR215##

In an atmosphere of hydrogen gas, the mixture solution of benzyl compound (190 mg) of Example 4, 10% Pd-carbon (30 mg), acetic acid (10 ml) and THF (4 ml) was stirred for 3 hours at room temperature.

The reaction solution was filtered off, and the filtrate was carried out azeotropic concentration by mixture of toluene-THF, and the azeotropic concentrate was recrystallized by mixture of ethyl acetate-hexane to give title compound (143 mg) having the following physical data.

TLC: Rf 0.56 (ethyl acetate: hexane=1:1);

IR: ν2700˜2400, 1750, 1680, 1600, 1340, 1290, 1200, 1160, 1110 cm⁻¹.

Hereinafter, by the same procedure of Example 5, using corresponding benzyl compound, compounds of the present invention described in the following Table VII were obtained.

                                      TABLE VII                                    __________________________________________________________________________      No.Example                                                                          ##STR216##          Name               TLC      or NMRIR                 __________________________________________________________________________                                                          (cm.sup.-1)                ##STR217##                                                                    5(1)                                                                                 ##STR218##         p-[N-(α-carboxyphenethyl)sulfamoyl] phenyl                               ester of pivalic acid                                                                             Rf 0.34 chloroform: methanol:                                                  cetic acid = 100:5:1)                                                                   δ 7.8(2H,d),                                                             7.4˜7.0(7H,m),                                                           .2(1H,b), 4.2(1H,b),                                                           .2˜3.0(2H,b),                                                            1.4(9H,s)                 5(2)                                                                                 ##STR219##         p-[N-(α-carboxybenzyl)sulfamoyl] phenyl                                  ester of pivalic acid                                                                             Rf 0.44 (chloroform: methanol:                                                  acetic acid                                                                            δ 7.8(2H,d),                                                             7.35(5H,bs),                                                                   7.15(2H,d), 5.75(1H,d                                                          ), 5.15(1H,d),                                                                 1.35(9H,s)                5(3)                                                                                 ##STR220##         p-[N-(o-carboxyphenyl)sulfamoyl] phenyl ester of                               pivalic acid       Rf 0.37 (chloroform: methanol:                                                  acetic acid                                                                            δ 8.2˜7.0                                                          (8H,m), 5.5(1H,b),                                                             1.35(9H,s)                5(4)                                                                                 ##STR221##         2-methyl-4-[N-(o-carboxyphenyl) sulfamoyl]phenyl                               ester of pivalic acid                                                                             Rf 0.25 (chloroform: methanol:                                                  acetic acid                                                                            δ 8.05(1H,d),                                                            7.9˜7.3(5H,m),                                                           .3˜7.0(2H,m),                                                            2.2(3H,s), 1.35(9H,s)     5(5)                                                                                 ##STR222##         2-methyl-4-[N-(2-carboxy-4- chlorophenyl)sulfamoy                              l]phenyl ester of pivalic acid                                                                     Rf 0.26 (chloroform:                                                          methanol: acetic acid =                                                        100:5:1) (CDCl.sub.3 +                                                                  CD.sub.3 OD) δ                                                           .0(1H,d), 7.8˜7                                                          .6(3H,m), 7.45(1H,d,d                                                          ), 7.1(1H,d),                                                                  2.2(3H,s), 1.4(9H,s)                                                           O                         5(6)                                                                                 ##STR223##         2-methyl-4-[N-(2-carboxy-4- methylphenyl)sulfamoy                              l]phenyl ester of pivalic acid                                                                    Rf 0.41 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .9˜7.5(4H,m),                                                            7.38(1H,d), 7.1(1H,d)                                                          , 2.35(3H,s),                                                                  2.2(3H,s), 1.35(9H,s)     5(7)                                                                                 ##STR224##         2-isopropyl-4-[N-(o-carboxyphenyl) sulfamoyl]phen                              yl ester of pivalic acid                                                                          Rf 0.32 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .0(1H,d), 7.9˜7                                                          .5(4H,m), 7.25(1H,d),                                                           7.1(1H,d), 3.0(1H,b)                                                          , 1.35(9H,s),                                                                  1.15(6H,d)                5(8)                                                                                 ##STR225##         2-isopropyl-4-[N-(2-carboxy-4- chlorophenyl)sulfa                              moyl]phenyl ester of pivalic acid                                                                 Rf 0.32 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .95(1H,d), 7.85.about                                                          .7.4(4H,m), 7.05(1H,d                                                          ), 3.0(1H,b),                                                                  1.35(9H,s), 1.15(6H,d                                                          )                         5(9)                                                                                 ##STR226##         2-methyl-4-[N-(2-carboxynaphthyl) sulfamoyl]pheny                              l ester of pivalic acid                                                                           Rf 0.33 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .6(1H,s), 8.05(1H,s),                                                           7.9˜7.3(6H,m),                                                           7.0(1H,d), 2.1(3H,s)                                                          , 1.35(9H,s)              5(10)                                                                                ##STR227##         2-methyl-4-[N-(2,5-dicarboxyphenyl) sulfamoyl]phe                              nyl ester of pivalic acid                                                                         Rf 0.26 (chloroform: methanol:                                                  acetic acid                                                                            CDCl.sub.3 +                                                                   CD.sub.3 OD) δ                                                           .3(1H,d), 8.0(1H,d),                                                           .8˜7.6(3H,m),                                                            7.03(1H,d), 2.2(3H,s)                                                          , 1.35(9H,s)              5(11)                                                                                ##STR228##         2-methyl-4-[N-(3-carboxypyridine-2- yl)sulfamoyl]                              phenyl ester of pivalic acid                                                                      Rf 0.48 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3 +                                                                  CD.sub.3 OD) δ                                                           .3(2H,m), 8.0(1H,s),                                                           .9(1H,d), 6.95(1H,d,d                                                          ), 2.25(3H,s),                                                                 1.35(9H,s)                5(12)                                                                                ##STR229##         2-methyl-4-[N-(2-carboxy-4- hydroxyphenyl)sulfamo                              yl]phenyl ester of pivalic acid                                                                   Rf 0.31 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3 +                                                                  CD.sub.3 OD) δ                                                           .7˜7.4(3H,m),                                                            7.32(1H,d), 7.1.about                                                          .6.8(2H,m), 2.15(3H,s                                                          ), 1.35(9H,s)             5(13)                                                                                ##STR230##         2,6-dimethyl-4-[N-(o-carboxyphenyl) sulfamoyl]phe                              nyl ester of pivalic acid                                                                         Rf 0.28 (ethyl acetate:                                                        hexane: acetic acid =                                                          10:20:0.5)                                                                              ν 3500˜2500,                                                          1750, 1660,1580,1480,                                                           1420,1340,1250,                                                               1150,1100                 5(14)                                                                                ##STR231##         2-methyl-4-[N-(2-carboxy-4- acetyloxyphenyl)sulfa                              moyl]phenyl ester of pivalic acid                                                                 Rf 0.33 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .8˜7.1(5H,m),                                                            7.0(1H,d), 2.3(3H,s),                                                           2.15(3H,s),                                                                   1.35(9H,s)                5(15)                                                                                ##STR232##         2-methyl-4-[N-(2-carboy-4- hexanoyloxyphenyl)sulf                              amoyl] phenyl ester of pivalic                                                                    Rf 0.33 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .75˜7.40(4H,m),                                                           7.15(1H,d,d),                                                                 6.95(1H,d), 2.45(2H,t                                                          ), 2.1(3H,s),                                                                  1.35(9H,s), 0.85(3H,t                                                          )                         5(16)                                                                                ##STR233##         2-methyl-4-[N-(2,5-dicarboxyphenyl) sulfamoyl]phe                              nyl ester of pivalic acid                                                                         Rf 0.37 (chloroform: methanol:                                                  acetic acid                                                                            ((CD.sub.3).sub.2                                                              SO) δ 7.98(2H,d                                                          ), 7.4˜7.2(3H,m                                                          ), 7.0(1H,d),                                                                  2.1(3H,s), 1.36(9H,s)     5(17)                                                                                ##STR234##         o-(3-methyl-4-pivaloyloxybenzene) sulfonylaminobe                              nzoyloxy acetic acid                                                                              Rf 0.33 (chloroform: methanol:                                                  acetic acid                                                                            (CDCl.sub.3) δ                                                           .0˜6.85(7H,m),                                                           .75(2H,s), 2.15(3H,s)                                                          , 1.35(9H,s)               ##STR235##                                                                    5(18)                                                                                ##STR236##         p-[N-(o-carboxyphenyl)carbamoyl] phenyl ester of                               pivalic acid       Rf 0.42 (ethyl acetate:                                                        hexane: acetic acid =                                                          10:20:0.5)                                                                              ν 1740,1680,1660,                                                           600,1590,1540,                                                                 1480,1440                 5(19)                                                                                ##STR237##         p-[N-(methyl-N-(o-carboxyphenyl) carbamoyl]phenyl                               ester of pivalic  acid                                                                           Rf 0.17 (ethyl acetate:                                                        hexane: acetic acid =                                                          10:20:0.5)                                                                              ν 1750,1720,1590,                                                           470,1440,1380             5(20)                                                                                ##STR238##         p-[N-(methyl-N-(m-carboxyphenyl) carbamoyl]phenyl                               ester of pivalic acid                                                                            Rf 0.15 methylene chloride:                                                    ethyl acetate                                                                           ν 1750,1720,1640,                                                           600,1580,1480,                                                                 1440,1370                 __________________________________________________________________________

EXAMPLE 6 p-[(N-methyl-N-phenyl)sulfamoyl]phenyl ester of pivalic acid ##STR239##

In an atmosphere of argon, THF solution (8 ml) of the compound of the present invention of Example 1 (1) (300 mg) was added to sodium hydride (37 mg) under cooling with ice, and the mixture was stirred for 2 hours.

Methyl iodide (66 μl) and hexamethylphosphoramide (HMPA) (1 ml) were added to the reaction solution, and the mixture was stirred for 30 minutes.

The reaction solution was extracted with ether, and the extract was washed with successive, water and saturated aqueous solution of sodium chloride.

And further, the solution was dried with sodium sulfate, and distilled off under reduced pressure to give the title compound (180 mg) having the following physical data.

TLC: Rf 0.61 (methylene chloride : ethyl acetate=30:1);

IR: ν1750, 1590, 1490, 1450, 1340 cm⁻¹.

Hereinafter, by the same procedure of Example 6, using corresponding derivative of pivlaic acid, the compounds of the present invention described in Table VIII were obtained.

                                      TABLE VIII                                   __________________________________________________________________________      ##STR240##                                                                     No.Example                                                                           ##STR241##          Name                TLC     or NMRIR                                                                      (cm.sup.-1)              __________________________________________________________________________     6(1)                                                                                  ##STR242##         p-[N-methyl-N-(p-tolyl)carbamoyl] phenyl ester                                 of pivalic acid     Rf 0.33 (methylene chloride:                                                    acetic acid                                                                           ν 1750,1640,1600,                                                            1510,1360,1200,                                                               (neat)                   6(2)                                                                                  ##STR243##         p-[N-methyl-N-(o-benzyloxy- carbonylphenyl)carba                               moyl]phenyl ester of pivalic acid                                                                  Rf 0.21 (methylene chloride:                                                    acetic acid                                                                           ν 1750,1720,1640,                                                            1600,1370,1250,                                                               (neat)                   6(3)                                                                                  ##STR244##         p-[N-methyl-N-(m- benzyloxycarbonylphenyl)carbam                               oyl] phenyl ester of pivalic acid                                                                  Rf 0.38 (methylene chloride:                                                    acetic acid = 30:1)             6(4)                                                                                  ##STR245##         p-[N-methyl-N-(pyridine-3-yl) carbamoyl]phenyl                                 ester of pivalic acid                                                                              Rf 0.44 (chloroform:                                                           methanol = 10:1)                                                                       ν 1750,1650,1480,                                                            1420,1380,1200,                                                               1110                     __________________________________________________________________________

EXAMPLE 7 3-hydroxy-4-[(N-methyl-N-pheyl)scarbamoyl]phenyl ester of pivalic acid ##STR246##

The mixture of methanol (5 ml) and triethylamine (0.3 ml) of the compound (83 mg) of the present invention obtained by procedure of Example 2 (112) was stirred for 3 hours at room temperature.

The reaction solution was extracted with ether, and the extract was washed successively with 1N-HCl, water, saturated an aqueous solution of sodium chloride.

The solution was dried with sodium sulfate, and distilled off under reduced pressure to give the title compound (68 mg) having the following physical data.

TLC : Rf 0.34 (methylene chloride:ethyl acetate=30:1);

NMR (CDCl3): δ7.0˜7.4(6H, m), 6.65(1H,d), 6.1(1H,2d), 3.5(3H,s), 1.3(9H,s).

EXAMPLES OF PREPARATIONS

The following components were admixed in conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient.

    ______________________________________                                         N-[o-(p-pivaloyloxybenzene)                                                                         5 g                                                       sulfonylaminobenzoyl]glycine                                                   Cellulose calcium glycolate                                                                         0.2 g                                                     (disintegrating agent)                                                         Magnesium stearate   0.1 g                                                     (lubricating agent)                                                            Microcrystaline cellulose                                                                           4.7 g                                                     ______________________________________                                     

What is claimed is:
 1. A compound of the formula: ##STR247## wherein Y represents a sulfonyl (--SO₂) group, R¹ and R², which may be the same or different, each represent,(1) a hydrogen atom, or (2) an alkyl group of up to 16 carbon atoms; R³ represents(1) a hydrogen atom, or (2) an alkyl group of up to 6 carbon atoms; and m represents an integer of up to 4; or non-toxic salts or acid addition salts thereof.
 2. A compound according to claim 1, which is p-(N-tertbutylsulfamoyl)phenyl ester of pivalic acid.
 3. A pharmaceutical composition for the prevention and treatment of pulmonary emphysema, atherosclerosis and rheumatoid arthritis, which comprises, as active ingredient, an effective amount of at least one compound of the formula (I) depicted in claim 1 wherein the various symbols are as defined in claim 1, and a pharmaceutically acceptable carrier. 